Nucleoside compounds are composed of a sugar moiety, typically ribose or 2-deoxyribose in naturally-occurring nucleosides, and a heterocyclic base which typically is adenine, guanidine, cytosine, thymine or uracil. Many nucleosides have basic amino substitution on the heterocyclic base and exhibit chemical reactivity characteristic of amino alcohols. The nitrogen atom of amino alcohols is frequently the most reactive and readily acylated functional group.
Nucleoside compounds and derivatives thereof have assumed an important role in the chemotherapy of viral and neoplastic diseases (see, e.g. P. L. Sarma et al., Curr. Top. Med. Chem. 2004 4:895-919; W. B. Parker et al., Curr. Opin. Invest. Drugs 2004 5(6):592-596). While nucleoside derivatives are frequently potent chemotherapeutic agents, their clinical use is often limited by suboptimal physical properties which result in poor pharmacokinetic profiles. Nucleoside prodrugs sometimes exhibit increased potency, bioavailability, stability which results in enhanced delivery of therapeutically effective amounts of the active moiety to the cellular target. Alkylation, acylation or other lipophilic modification of functional groups on the nucleoside often enhance passive diffusion through the intestinal wall (transcellular transport). Alternatively functional groups may be linked which are substrates for carrier-mediated transport systems resulting in an active transport of the prodrug. J.-L. Kraus et al., Curr. Med. Chem. 2003 10(18):1825-1846; P. Ettmayer et al., J. Med. Chem., 2004 47(10):2393-2404; K. Beaumont et al., Curr. Drug Metab. 2003 4:461-485; H. Bundgaard, Design of Prodrugs: Bioreversible derivatives for various functional groups and chemical entities in Design of Prodrugs, H. Bundgaard (ed) Elsevier Science Publishers, Amsterdam 1985; G. M. Pauletti et al., Adv. Drug Deliv. Rev. 1997 27:235-256; and K. Beaumont et al., Curr. Drug Metab. 2003 4:461-485).
One strategy for prodrug design applicable to nucleosides is acylation of the hydroxyl substituents on the sugar moiety. Selective tri-acylation of the sugar residues of uridines has been reported (H. B. Lassan et al., Nucleoside Nucleotides 1998 17(9-11):1851-1856 and C.-T. Chen et al., Org. Lett. 2001 3(23):3729-3732.). Selective O-acylation of hydroxy groups of thymidine and uridine nucleosides under phase transfer conditions has been reported (M. Sekine, Nat. Prod. Lett. 1993 1(4):251-256). Nucleosides substituted with heterocyclic bases with an amino substituent are less likely to undergo such selective transformations. The preparation of 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)cytosine hydrochloride (ara-C HCl) utilizes a two-step process comprising peracetylation and selective hydrolysis of the N-acetyl linkage with anhydrous ZnBr2, MeOH and CHCl3 (M. Bobeck et al., J. Med. Chem. 1987 30(11):2154-2157). A similar two-strategy for preparing tri-O-acyl derivatives of 4-amino-1-((2R,3R,4S,5R)-5-azido-3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-1H-pyrimidin-2-one was reported by J. A. Martin et al., in U.S. Pat. No. 6,846,810 filed Nov. 19, 2003. Selective O-acylation of the sugar substitutents of cytosine-containing nucleosides under acidic conditions has been reported to result in O-acylation of cytidine, 2′-deoxycytidine and ara-C, R. G. Breiner et al., J. Med. Chem. 1990 33(9):2596-2602; A. P. Martinez et al., J. Med. Chem. 1966 9(2):268). While not wishing to be limited by a mechanistic hypothesis, these transformations were carried out under acidic conditions which protonate the amino substituent on the base and thereby suppress N-acylation. Selective O-acylation of guanosine and deoxyguanosine nucleosides with acetic anhydride in the presence of MeCN/TEA/DMAP (catalytic quantity) has been reported (A. Matsuda et al., Synthesis 1986 385-386). Selective O-acylation of cytidine under similar conditions has been reported (M. A. Zinni et al., J. Mol. Cat. B 2004 29:129-132). While these conditions result in some selective O-acylated product, the yields of O-acylated product are not acceptable.